16 (substituted methyl) pregnenolones and derivatives



United States Patent 16(SUBSTITUTED METHYDPREGNENOLONES AND DERIVATIVES Robert H. Mazur, Evanston, and John A. Celia, Skokie, 111., assignors to G. D. Searle & Co., Chicago, 111;, a corporation of Delaware No Drawing. Application August 9, 1956 Serial No. 603,183

7 Claims. (c1. zen-397.3

This invention relates to p'regnenolone derivatives wherein there is present a l6-methyl radical substituted by an acid residue, said derivatives being optionally esterified in position 3, or oxidized thereat to corresponding ketones. More particularly, this invention relates to compounds of the formula wherein R and R" are variously cyano, acetyl, or ethoxycarbonyl radicals; X is a hydroxymethylene, (lower alkanoyl)oxymethylene, or carbonyl radical; and the carbon atom in position number 5 is doubly bonded to solely one of the carbons at 4 and 6.

83/ lower alkanoyl in the foregoing formula is meant ll Olower alkyl the lower alkyl radicals contemplated being methyl ethyl,

propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, sec-n-pentyl, primary isopentyl, sec-isopentyl, tertpentyl, hexyl, and similar C,,H radicals such that n is a positive integer amounting to less than 7.

It will be apparent to those skilled in the art that the compounds of this invention constitute a relatively. homo- "geneous chemical grouping in that they are,'unexceptionably, 3-oxygenated pregnen-ZO-ones distinguished by the ncorporation at carbon atom 16 of a particular kind of organic radical, namely, an acid radical derived from the limited class of substances made up of The latter substances are all characterized by the presence ice of. two electronegative groups attached to methylene, and share a familial capacity for giving up protons under the influence of alkali or alkali metals. Moreover, such substances have in common the fact that they are typical of compounds susceptible to Michael condensation, viz., base-catalyzed addition to the a,,8 double bond of a conjugated unsaturated ketone. Thus, whether viewed wholly or in part, the compounds to which this application relates will be seen topartake of that community of chemical properties essential to their generic treatment herein.

The claimed compounds are valuable because of their desirable pharmacological activity. For example, the subject compounds are anti-inflammatory agents, being adapted to protection against the hyperemia. associated with specific types of iritis. Additionally, the compounds of this invention have anti-infective properties: they inhibit in particular species, cortisone-induced enhancement of the adverse effects of Coxsackie virus. Still further, the compounds here disclosed are useful anabolic-androgenic agents: they promote nitrogen retention, contribute to muscle growth, and tend to stimulate the development of secondary sex characteristics in males.

The compounds of this invention are relatively insoluble in water, but may be dissolved in such common organic solvents as alcohol, chloroform, ethyl acetate, and the like.

The subject compounds may be administered in solid" form as tablets or capsules; dissolved in aqueous media, they may be given parenterally.

' p The 3-acetoxy compounds to which this invention re- Iates are Conveniently prepared by interaction at substan tially room temperatures of l6-dehydropregnenolone acetate with an alkali metal and an appropriate member of the group, malononitrile, acetylacetone, diethyl malonate, acetylacetonitrile, ethyl cyanoacetate, and ethyl acetoacetate, there being provided a liquid alcoholic medium (1) where the reagents would otherwise comprise a solid mixture or (2) where it is preferred to insure in situ formation of alkoxide for catalytic purposes. The corresponding 3-hydroxylated materials of the invention are obtained from the acetoxy compounds by mild alkaline hydrolysis, and may in turn be treated according to usual techniques with an acid anhydride or chloride of choice to give a particular ester hereof. Alternatively, the 3-hydroxy compounds may be subjected to Oppenauer oxidation to the respective 3-ketonic products claimed.

The following examples describe in detail certain of the compounds illustrative of this invention, and methods which havebeen devised for their preparation. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. In the examples hereinafter detailed, temperatures are given in degrees centigrade C.) and r'elativeamounts of materials in parts by weight, except as otherwise noted.

' Example 1 3,8-dcetoxy-16-dicyanomethylpregn-5-en-20-0ne.-To a solution of 13 parts of potassium in 335 parts of tertbutyl alcohol at room temperatures is added 22 parts of malononitrile. There is then introduced parts of 3p-acetoxypregna-5,16-diene-20-one, same being washed 3 l i into the reaction vessel with approximately 335 p of tert-butyl alcohol. The resultant mixture is agitated and refluxed at the boiling point of the solvent in a nitrogen atmosphere overnight. Neutralization is effected with 20 parts of acetic acid, following which solvent is evaporated in vacuo. The residue is extracted into chloroform, and the chloroform extract is then washed with water and finally dried over anhydrous sodium sulfate. Chloroform is distilled oft; and residue is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. There is obtained by this means SB-acetoxy-l6-dicyanomethylpregn-S-en-ZO- one, which, recrystallized from anhydrous alcohol, melts in the range 160-190 C. The product is a mixture of the a and {3 dicyanomethyl isomers. It has the formula 16 dicyanomethyl 3B hydroxypregn en 20- 0ne.-To 1000 parts of anhydrous ethyl alcohol are added 100 parts of Elfl-acetoxypregna-S,16-dien-20-one, 14 parts of sodium, and 40 parts of malononitrile. The resultant mixture is agitated at room temperatures until a clear solution results, whereupon said solution is allowed to stand undisturbed at room temperatures for 4 the product with starting material melts at 186-198 C. The product has the formula (3H3 C=O CH3 l i TIT-MON),

Example 4 318 ac etoxy 16 diacetylmethylpregn 5 en 20- one.--Solution of 3 parts of sodium in 2 parts of acetylacetone is effected by heating with agitation under a nitrogen atmosphere at 100 C. To the chilled solution is added 36 parts of powdered 3/8-acetoxypregna- 5,16-dien-20-one, same being washed into the reaction vessel with an additional 100-200 parts of acetylacetone. The resultant mixture is agitated at 90-100" C. under a nitrogen atmosphere for l6-24,hours, during which time suspended solids dissolve. The reaction mixture is then cooled and acidified with 12 parts of acetic acid. The bulk of excess acetylacetone is removed by distillation in vacuo, and the residue is quenched in about 200 parts of water. The organic phase is extracted into ether, and the ether extract is washed with water and i then dried over anhydrous sodium sulfate. Solvent is evaporated; and the residue is chromatographed on silica I gel, using benzene and ethyl acetate as developing sol- 24 hours. The solution is then diluted with a large N volume of water, whereby hydrolysis of the S-acetoxyl group is accomplished. Extraction into chloroform, followed by evaporation of solvent and chromatography of the residue on silica gel-using benzene and ethyl acetate as developing solvents-aifords lfi-dicyanomethyl- 35-hydroxypregn-5-en-20-one, which crystallizes from ethyl alcohol as hard, iridescent prisms melting at 206- 209 C. The product has the formula.

(3113 C=O CH:

OH(CN):

Example 3 16 dicyanomethylpregn 4 -ene 3,20 di0ne.A mixture of 17 parts of 16-dicyanomethyl-Sfl-hydroxypregn-S-en-ZO-one, 170 parts of freshly distilled cyclohexanone, and 100 parts of 20% (w./v.) aluminum isoproproxide in dry toluene is added to 1500 parts of dry toluene; and the resultant mixture is refluxed at the boiling point of the solvent for two hours. After cooling, the mixture is added to 1500 parts of 50% aqueous potassium sodium tartrate, whereupon steam distillation is efiected to remove volatile organics; The crude product remaining in the distilland is extracted into chloroform, the extract is stripped of solvent by evaporation, and the residue is'chromatographed on silica gel. Elution with a mixture consisting of 10% ethyl acetate in benzene gives 16-dicyanomethylpregn-4-ene-3,ZO-dione, which, recrystallized from amixture of benzene and gyclohexaua-meltsat 206-:210 C. A 1:1 mixture of vents. The 3,8-acetoxy-16-diacetylmethylpregn-5-en-20- one thus obtained is further purified by recrystallization from anhydrous alcohol. The product melts at 182-186 C. and has the formula 16-diacetylmethyl-3,8-hydroxypregn-5-en-20-one.-To a solution of 1 part of sodium in 345 parts of methyl alcohol is added 1 part of water followed by 20 parts of 3 3-acetoxy-l6-diacetylmethylpregn-5-en-20-one. The resultant mixture is heated under reflux at the boiling point or the solvent until neutral to phenolphthalein. The mixture is then evaporated to dryness in vacuo, whereupon the residue is extracted into chloroform. The chloroform extract is washed with water and then dried over anhydrous sodium sulfate. Chloroform is removed by distillation, leaving the desired 16-diacetylmethyl-3,B-hydroxypregn-S-en-ZO-one as residue.

a solu- I6 dit1cetylmettzylpregn-4-ene-3,20-diorie.-To

The product has the;

V en-ZO-one in 100 parts of dry toluene and 12 parts of freshly distilled cyclohexanone refluxing at the boiling point is added a solution of 3 parts of aluminum isopropoxide in 50 parts of dry toluene. Heating at the boiling point is continued for 15 minutes, with agitation, at which point approximately 30 parts of a saturated aqueous solution of Rochelle salt is introduced. Volatile organics are removed by steam distillation, and product is extracted from the distilland with chloroform. The chloroform extract is washed with water and finally dried over anhydrous sodium sulfate. Solvent is stripped by vacuum distillation; and the residue is then chromatographed on silica gel, using benzene-and ethyl acetate as developing solvents. The resultant l6-diacetylmethylpregn-4-ene-3,20-dione has the formula C=O CH:

Example 7 3,3 acetoxy 16 dz'(etlz0xycarbonyl) methylpregn en-20-0ne..Using the. technique of Example 4 but replacing acety-lacetone therein with like quantities of diethyllmalonate, there are obtained'both the 0!. and ,8 (at carbon atom; 16) isomers of 3B-acetoxy-l6-di(ethoxycarbonyl)methylpregmS-enr20 one. The one isomer, crystallized from 80% aqueous alcohol, melts at 122-124" C. The second isomer, crystallized from 70% aqueous alcohol, melts at; 139-140 C. The-products are represented by the formula =0 CHI Example 8 0 0 OH: I

Example 9 16 di(ethoxycarbonyl)methylpregn 4 ene 3,20 diane.-Using the technique of Example 6 but replacing the diacetylmethylpregnene therein with a like quantity of the di(ethoxycarbonyl)methylpregnene of the preceding 6 Example 8, there is obtained l6'-di(ethoxycarbonyl)methylpregn -4-ene-3,2,0-dione, of the formula cnoo o elm),

Example 10 16 [a (ethoxycarbonyl)cyanomethyl] 3B hydroxypregn-S-en-20-one.-To a solution of 14 parts of sodium and 68 parts of ethyl cyanoacetate in 1000 parts of anhydrous ethyl alcohol is added 107 parts of 3 8- acetoxypregna-S,l6-dien-20-one. The resultant mixture is stirred until a clear solution is obtained, and the latter is allowed to stand atroom temperatures for three days. The solution is then neutralized with acetic acid, diluted with water, and finally subjected to chloroform extraction to remove the desired product. Solvent is evaporated from the extract, whereupon theresidue is chromatogarphed on silica gel, using benzene and ethyl acetate as developing solvents. Crystallization of the l6-[a-(ethoxycarbonyDcyanomethyl] 3/8 hydroxypregn 5 en- 20-one thus isolated from ethyl acetate atfords the product in clusters of short needles melting at l94-l96 C.

The product has the formula CH(ON) 00 0 02115 Example 11 IG-Ia-(ethoxyca rbonyl)cyanomethyl] pregn 4 ene- 3,20-dione.--Approximately 30 parts of 16-[otetlzoxycarbonyl) cyanomethyl]-3/3 hydroxypregn-5 en 20 one in 1000 parts of dry toluene is oxidized by adding 300 parts of cyclohexanone and 300 parts of 20% (w./v.) aluminum isopropoxide in toluene and heating under reflux for 1 /2 hours at the boiling point. The reaction mixture is then cooled and treated with 1000 parts of 50% aqueous potassium sodium tartrate, following which the mixture is steam distilled to remove volatile organic components. The distilland is extracted with chloroform, solvent subsequently being evaporated in vacuo and the residue chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. Crystallization of the product thus isolated from ethyl acetate gives thick needles melting at 2l3-2l6 C. The material so obtained is 16-[a-(ethoxycarbonyl)cyanomethyl] pregn-4- ene-3,20-dione, having the formula GH(ON) CO 0 CzHs Example 12 16 [ct-(acetyl) ethoxycarbonylmethyl] 3p hydroxypregn-5-en-20-one.-Using the technique of Example 5 lbutreplacing the diacetyl compound therein with 20 parts of '3fi-acetoxy 16 [a (acetyl) ethoxycar'bonylmethyl] pregn-S-en-ZO-one, there results 16-[a-(acetyl) ethoxycarbonylrnethyl]-3fl-hydroxypregn-S-en-ZO-one, :of the formula I I OH:

: ]CH(COCHB)OOOCIHI Example 14 16-[a-(acetyl)ethoxyoarbonylmethyi]pregn 4 eneplacing the diacetyl compound used-therein as a starting naaterial with 2 parts of 16-[a-(acety1)ethoxycarbonylmethyl]-3fl-hydroxypregn-S-en-ZO-one, there is obtained 3,20-dione.Using th e' technique' of Example 6 but redione, haying the formula 8 16-[a-(acetyl)ethoxycarbonylmethyllpregn 4 cne-3,20-

What'is claimed is: I 1. A compound of the formula wherein the 16-methyl substituents, R and R" are selected from the group consisting of cyano, acetyl, and ethoxycarbonyl radicals; X is selected from the group consisting of p hydroxymethylene, ,B-(lower alkanoyl)- oxymethylene, and carbonyl radicals; and there is a double bond situate in the 4(5) 1 position when Xis' carbonyl, otherwise a 5(6) double bond is present.

2. 16-dicyanomethy1-35-hydroxypregn-5-en-20-one. 3. 3p-acetoxy-16 di(e thoxycarbonyl) methylpregn 5 4. Sp-aoetoxy-l6-diacetylmethylpregnJ-en-ZO-one, v 5. 16-[u-(ethoxycarbonyl) cyanomethyl] 1 SB-hydroxypregn-S-en-ZO-one.

6. Sfl-acetoxy-lfi-[a (acetyl)ethoxycarbonylmethyllpregn-S-en-ZO-one.

7. 16-dicyanomethylpregn-4-ene-3,ZO-dione.

References Cited in the file of this patent UNITED STATES PATENTS Bruson Feb. 12, 1946 Mazur -t. Dec. 24, 1957 Patent No. 2332,655 April 12- 1960 Robert H. Mazur et a1.

printed specification ied that error appears in the that the said Letters tent requiring correction and rreoted below.

left-hand portion of the iormula toad of as in the patent:

It is hereby certif of the above numbered pa Patent should read as oo Column 6, lines 72 to 75, should appear as shown below ins Signed and sealed this 20th day of September 1960.

(SEAL) Attest:

KARL AXLINE ROBERT C. WATSON Attesting Officer Commiss ioner of Patents 

1. A COMPOUND OF THE FORMULA 